1. Field of the Invention
This invention relates to a process for preparing and purifying 6-ethylamino-2-picoline, an intermediate for a method of synthesizing nalidixic acid.
2. Description of the Prior Art
The various known methods of preparing 6-ethylamino-2-picoline usually result in the production of the desired compound together with some starting material, e.g., 6-amino-2-picoline or 6-acetamido-2-picoline, and/or one or more by-products, e.g., 6-diethylamino-2-picoline, ring-hydrogenated by-products using certain reducing agents such as lithium aluminum hydride and sodium borohydride. Separation of the desired 6-ethylamino-2-picoline from the starting material and/or by-product(s) is effected by various means, e.g., vacuum distillation, selective recrystallization, selective reaction of the starting material or by-product with an appropriate reagent and separation of the resulting derivative, and the like.
The Koei Japanese Patent Publication No. 15269/74, published Apr. 13, 1974, which was based on Application No. 16282/71, filed Mar. 20, 1971, describes a process for producing 6-ethylamino-2-picoline, characterized by catalytically hydrogenating 6-amino-2-picoline in liquid phase in the presence of an excess of acetaldehyde. By-product 6-diethylamino-2-picoline is removed by fractional distillation under high vacuum.
The Mitsubischi Chemical Industries, Ltd. provisional Japanese Patent Publication No. SHO49-108080, published Oct. 14, 1974 and based on Application No. SHO48-21945, filed Feb. 23, 1973, describes a process for the purification of 6-ethylamino-2-picoline by heating 6-ethylamino-2-picoline containing starting material 6-amino-2-picoline with an orthoformate in the presence of a weak acidic catalyst and separating by distillation the unreacted 6-ethylamino-2-picoline from the reaction products of 6-amino-2-picoline and an orthoformate, namely, N,N'-bis(6-methyl-2-pyridine)formamidine or alkyl (6-methyl-2-pyridyl)-formimidate.
The Kohjin Co., Ltd., Japanese Provisional Patent Publication No. 50-100064/75, published Aug. 8, 1975 and based on Application No. 49-6071/74, filed Jan. 11, 1974, discloses that the starting material, 6-ethylamino-2-picoline, used for the invention described therein can be prepared by reducing 6-acetamido-2-picoline with lithium aluminum hydride. No experimental details are given in this Kohjin patent publication for preparing 6-ethylamino-2-picoline, but it appears that the reduction of 6-acetamido-2-picoline with lithium aluminum hydride most likely would produce a mixture of the final product, some starting material, and probably one or more ring-hydrogenated by-product(s).
The Koei Chemical Co., Ltd., British patent specification No. 1,338,023, published Nov. 21, 1973, shows in Example 2 the use of "6-methyl-2-ethylaminopyridine" (same as 6-ethylamino-2-picoline) as an intermediate in preparation of nalidixic acid.